Exploring the reason for increased activity of SHP2 caused by D61Y mutation through molecular dynamics

Wang, Ruirui; Ma, Ying; Du, Shaowu; Li, Weiya; Sun, Ying-Zhan; Zhou, Hui; Wang, Run‐Ling

doi:10.1016/j.compbiolchem.2018.10.013

Cited by 13 publications

(8 citation statements)

References 60 publications

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“…Thus, PTPN11 is recognized as the first proto-oncogene . However, the activation mechanism for the following mutations has been explored using MD simulation by Wang et al − In the present study, we have explored the activation mechanism for the first time, induced by GOF-mutation (E76Q) in SHP2 protein using essential dynamics simulation approaches. This mutation has been identified in exon 3 with some additional mutations that encrypt the N-SH2 regulatory domain.…”

Section: Introductionmentioning

confidence: 94%

Gain-of-Function SHP2 E76Q Mutant Rescuing Autoinhibition Mechanism Associated with Juvenile Myelomonocytic Leukemia

Rehman

Rafiq

Rahman

et al. 2019

J. Chem. Inf. Model.

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Juvenile myelomonocytic leukemia (JMML) is an invasive myeloproliferative neoplasm and is a childhood disease with very high clinical lethality. The SHP2 is encoded by the PTPN11 gene, which is a nonreceptor (pY)-phosphatase and mutation causes JMML. The structural hierarchy of SHP2 includes protein tyrosine phosphatase domain (PTP) and Src-homology 2 domain (N-SH2 and C-SH2). Somatic mutation (E76Q) in the interface of SH2-PTP domain is the most commonly identified mutation found in up to 35% of patients with JMML. The mechanism of this mutant associated with JMML is poorly understood. Here, molecular dynamics simulation was performed on wild-type and mutant (E76Q) of SHP2 to explore the precise impact of gain-of-function on PTP’s activity. Consequently, such impact rescues the SHP2 protein from autoinhibition state through losing the interface interactions of Q256/F7 and S502/Q76 or weakening interactions of Q256/R4, Q510/G60, and Q506/A72 between N-SH2 and PTP domains. The consequences of these interactions further relieve the D′E loop away from the PTP catalytic site. The following study would provide a mechanistic insight for better understanding of how individual SHP2 mutations alter the PTP’s activity at the atomic level.

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Section: Introductionmentioning

confidence: 94%

Gain-of-Function SHP2 E76Q Mutant Rescuing Autoinhibition Mechanism Associated with Juvenile Myelomonocytic Leukemia

Rehman

Rafiq

Rahman

et al. 2019

J. Chem. Inf. Model.

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“…To have a better understanding of the dynamics of the three RuBisCO isoforms, cross-correlation analysis (DCCM) was used to evaluate the motions (shifts) of alpha (Cα) carbon atoms in the MD simulations of all systems [ 56 ]. Additionally, it provides useful information regarding the mutation effect on protein dynamics by analyzing how atomic shifts were correlated [ 57 , 58 ], and it was constructed using the Bio3D package from R-Project [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

“…In Figure 4, the eNMA shows the consensus fluctuations are highlighted and reveal a conserved pattern among species and RuBisCO forms (Figure 4a,b). The three isoforms show a greater fluctuation in the N-terminal domain spanning the amino acid residues (51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68) between the secondary elements αB and βC (Figure 4a), which are functionally relevant for RbcL. Likewise, RuBisCO form III presents greater fluctuation (≥3 Å) with respect to form I and II (Figure 4a,b).…”

Section: Stability and Flexibility Evaluation Of Rubisco Formsmentioning

confidence: 99%

An Insight of RuBisCO Evolution through a Multilevel Approach

Camel

Zolla

2021

Biomolecules

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RuBisCO is the most abundant enzyme on earth; it regulates the organic carbon cycle in the biosphere. Studying its structural evolution will help to develop new strategies of genetic improvement in order to increase food production and mitigate CO2 emissions. In the present work, we evaluate how the evolution of sequence and structure among isoforms I, II and III of RuBisCO defines their intrinsic flexibility and residue-residue interactions. To do this, we used a multilevel approach based on phylogenetic inferences, multiple sequence alignment, normal mode analysis, and molecular dynamics. Our results show that the three isoforms exhibit greater fluctuation in the loop between αB and βC, and also present a positive correlation with loop 6, an important region for enzymatic activity because it regulates RuBisCO conformational states. Likewise, an increase in the flexibility of the loop structure between αB and βC, as well as Lys330 (form II) and Lys322 (form III) of loop 6, is important to increase photosynthetic efficiency. Thus, the cross-correlation dynamics analysis showed changes in the direction of movement of the secondary structures in the three isoforms. Finally, key amino acid residues related to the flexibility of the RuBisCO structure were indicated, providing important information for its enzymatic engineering.

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“…Molecular dynamics (MD) simulations are particularly suited to characterize the conformational heterogeneity of proteins in solution, and were employed in several articles to characterize various aspects related with SHP2 regulation (an overview of these studies is provided in Table S1 ). However, standard or enhanced sampling MD simulations of SHP2 pathogenic variants or of SHP2/phosphopeptide complexes starting from the autoinhibited state observed no dramatic variations of the interdomain arrangement [29] , [39] , [53] , [54] , [55] , [56] , [57] , [58] . This finding is not surprising, considering that stopped-flow measurements [45] and single molecule FRET experiments [46] , [47] indicate that interconversion between the autoinhibited and active states takes place in the seconds time-range; transitions with such high barriers are not amenable to sampling by currently reachable MD timescales.…”

Section: Introductionmentioning

confidence: 99%

Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state

Calligari

Santucci

Stella

et al. 2021

Computational and Structural Biotechnology Journal

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Exploring the reason for increased activity of SHP2 caused by D61Y mutation through molecular dynamics

Cited by 13 publications

References 60 publications

Gain-of-Function SHP2 E76Q Mutant Rescuing Autoinhibition Mechanism Associated with Juvenile Myelomonocytic Leukemia

Gain-of-Function SHP2 E76Q Mutant Rescuing Autoinhibition Mechanism Associated with Juvenile Myelomonocytic Leukemia

An Insight of RuBisCO Evolution through a Multilevel Approach

Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state

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